The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin
Abstract
:1. Introduction
2. Materials and Methods
2.1. Drugs, Chemicals, and Supplements
- Streptozotocin (STZ), a chemical powder supplied as 1 g vial, was obtained from Sigma-Aldrich Company (St. Louis, Mo, USA).
- Sitagliptin, in the form of JANUVIA® 100 tablet was obtained from Merck Sharp and Dohme Ltd. (Pavia, Italy). Each JANUVIA® 100 tablet was ground and dissolved in 10 mL solution of 0.5% carboxymethyl cellulose (CMC), and afterward shaken to obtain a suspension form (10 mg/mL).
- Metformin, in the form of GLUCOPHAGE® 500 mg tab, was purchased from Minapharm (Cairo, Egypt) under license of Merck Santé France. Each Metformin 500 mg tablet was ground and dissolved in 10 mL solution of 0.5% CMC, and afterward shaken to obtain a suspension form (50 mg/mL).
- Citric acid, sodium citrate, and sodium carboxymethyl cellulose (Na-CMC) were obtained from ADWIC CO. (Cairo, Egypt). Citric acid and sodium citrate were used for the preparation of the citrate buffer.
- The diet ingredients such as lard and soybean oil were purchased from commercial sources.
2.2. Animals
2.3. Induction of Type 2 Diabetes Mellitus
2.4. Experimental Design
- Group 1: Normal control rats were fed a basal diet, received an equivalent volume of citrate buffer solution (parallel to STZ), through the same route of administration.
- Group 2: untreated diabetic rats. The animals of this group were subdivided into 2 subgroups, 5 rats received no treatment (subgroup 2a), and the remaining 5 rats received CMC, orally for 4 weeks (subgroup 2b), parallel to sitagliptin and metformin.
- Group 3: sitagliptin-treated diabetic rats were treated with sitagliptin (10 mg/kg/day) via oral gavage for 4 weeks.
- Group 4: metformin-treated diabetic rats were treated with metformin (200 mg/kg/day) via oral gavage for 4 weeks.
- Group 5: both combined-treated diabetic rats received both sitagliptin (10 mg/kg/day) and metformin (200 mg/kg/day) via oral gavage for 4 weeks.
2.5. Blood Glucose Tolerance Test (OGTT)
2.6. Biochemical Profile Assays
2.7. Histological Procedures
- Hematoxylin and eosin (H&E) according to previously stated protocols [22].
- Immunohistochemical techniques, using the peroxidase-labeled streptavidin-biotin method, according to previously demonstrated protocols [23].Immunohistochemical staining was applied for the detection of insulin antibody (INS05 (2D11-H5)). The primary antibody used was mouse monoclonal insulin antibody (Labvision Corporation, Fremont, CA, USA). It was supplied at a dilution of 0.5–1.0 µg/mL and incubated with the slides for one hour at room temperature.Immunohistochemical staining for the detection of the caspase-3 antibody as a marker of apoptosis. The primary antibody used was rabbit polyclonal caspase-3 antibody (Labvision Corporation, Fremont, CA, USA). It was supplied at a dilution of 1:100 and incubated with the slides for one hour at room temperature.Immunohistochemical staining for the detection of inducible nitric oxide synthase (iNOS) antibody as a marker of inflammation. The primary antibody used was rabbit polyclonal iNOS antibody (Labvision Corporation, Fremont, CA, USA). It was supplied at a dilution of 1 µg/mL and incubated with the slides for one hour at room temperature.
2.8. Histomorphometric Analysis
- Assessment of the islet number and islet size: For each study group, the islets were counted, and islet size was evaluated in 10 different, randomly selected microscopic fields, using lower magnification. Then, the mean islet number per field and mean islet size were calculated for each group of animals. The number of islets was expressed as N/10 mm2 of the pancreatic parenchyma, according to Noor et al. [24]. For the islet size, the maximum diameter of the islet was selected by comparing all possible radii diameters per islet and choosing the greatest according to previous work [4].
- Evaluation of the area % of insulin, caspase-3, and iNOS immunostaining: They were measured in 10 non-overlapping high power fields, using the interactive measurements menu. The brown coloration of the immunoreaction was covered automatically by a blue mask (binary image). The area of this binary image was then calculated, which reflected the positively stained cells for insulin, caspase-3, and iNOS.
2.9. Statistical Analyses
3. Results
3.1. Mortality, Food Intake, Water Intake, and Changes in Body Weight, Pancreas Weight, and Pancreas Weight to Body Weight Ratio
3.2. Glucose Homeostasis Parameters
3.3. Lipid Profile
3.4. Serum Lipase
3.5. Islet Cells Morphology and Pancreatic Acini
3.6. Immunohistochemical Observations
3.7. Histomorphometric Results
3.7.1. The Mean Islet Number and Islet Size
3.7.2. Area Percent of Insulin Immunoreactivity
3.7.3. Area Percent of Caspase-3 Immunoreactivity
3.7.4. Area Percent of iNOS Immunoreactivity
4. Discussion
5. Conclusions
Author Contributions
Acknowledgments
Conflicts of Interest
References
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Stages | Days | Events | |
---|---|---|---|
HFD feeding | D0-D21 |
| |
STZ injection | D22 | After overnight fasting of the animals, STZ was injected once intraperitoneally at a dose of 40 mg/kg. | |
Diabetes mellitus | D32 |
| |
Initiation of treatment | D32 | All treatment started on the 10th day after STZ injection and continued for 4 consecutive weeks:
| |
OGTT | D60 | At the end of the treatment period (4 weeks), an oral glucose tolerance test (OGTT) was done. | |
End of experiment | D60 | At the end of the treatment period (4 weeks) and 8 h after performing the OGTT:
|
Groups | Body Weight (g) | Pancreas Weight (g) | Pancreas to Body Weight Ratio (%) | ||
---|---|---|---|---|---|
Time (weeks) | Time (weeks) | Time (weeks) | |||
0 | 2 | 4 | 4 | 4 | |
Normal control | 245.15 ± 9.79 | 261.88 ± 9.62 | 296.75 ± 9.08 | 0.800 ± 0.049 | 0.27 ± 0.014 |
Diabetic | 261.56 ± 8.77 a | 305.52 ± 11.33 a | 341.80 ± 11.27 a | 0.462 ± 0.026 a | 0.14 ± 0.008 a |
Sitagliptin | 262.22 ± 13.68 a | 282.25 ± 10.58 ab | 318.66 ± 8.97 ab | 0.713 ± 0.411 abd | 0.22 ± 0.017 abd |
Metformin | 261.91± 11.08 a | 290.51 ± 12.51 ab | 318.40 ± 8.65 ab | 0.497 ± 0.013 ab | 0.16 ± 0.006 ab |
Combined | 262.74 ± 11.68 a | 279.30 ± 16 ab | 309.20 ± 9.19 abc | 0.802 ± 0.023 bc | 0.26 ± 0.009 bc |
Groups | Serum Insulin (μU/mL) | HOMA-IR |
---|---|---|
Normal control | 13.91 ± 2.33 | 3.90 ± 0.71 |
Diabetic | 10.44 ± 2.04 a | 7.35 ± 1.49 a |
Sitagliptin | 10.93 ± 1.86 a | 7.73 ± 1.23 a |
Metformin | 11.07 ± 1.99 a | 7.42 ± 1.37 a |
Combined | 10.28 ± 2.01 a | 7.70 ± 1.37 a |
Groups | Cholesterol (mg/dL) | Triglycerides (mg/dL) | Lipase (U/L) |
---|---|---|---|
Normal control | 111.92 ± 5.07 | 64.25 ± 3.40 | 514.50 ± 19.80 |
Diabetic | 161.80 ± 8.35 a | 138.30 ± 8.63 a | 517.55 ± 19.82 |
Sitagliptin | 160.70 ± 6.55 a | 137.90 ± 7.48 a | 516.70 ± 16.89 |
Metformin | 160.43 ± 7.54 a | 137.85 ± 8.33 a | 518 ± 19.64 |
Combined | 159.96 ± 8.19 a | 137.20 ± 8.35 a | 517.30 ± 14.47 |
Groups | Cholesterol (mg/dL) | Triglycerides (mg/dL) | Lipase (U/L) |
---|---|---|---|
Normal control | 111.31 ± 5.14 | 64.10 ± 3.41 | 515.35 ± 19.90 |
Diabetic | 161.35 ± 6.68 a | 137.70 ± 8.29 a | 518.05 ± 19.54 |
Sitagliptin | 119.10 ± 9.68 abc | 71.70 ± 6.44 ab | 516.90 ± 16.96 |
Metformin | 128.95 ± 10.12 ab | 70.36 ± 5.04 ab | 517.95 ± 18.64 |
Combined | 113 ± 7.16 bc | 63.67 ± 7.32 bd | 517.23 ± 17.36 |
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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Shawky, L.M.; Morsi, A.A.; El Bana, E.; Hanafy, S.M. The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin. Biology 2020, 9, 6. https://doi.org/10.3390/biology9010006
Shawky LM, Morsi AA, El Bana E, Hanafy SM. The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin. Biology. 2020; 9(1):6. https://doi.org/10.3390/biology9010006
Chicago/Turabian StyleShawky, Lamiaa M., Ahmed A. Morsi, Eman El Bana, and Safaa Masoud Hanafy. 2020. "The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin" Biology 9, no. 1: 6. https://doi.org/10.3390/biology9010006